全文获取类型
收费全文 | 568篇 |
免费 | 48篇 |
出版年
2022年 | 5篇 |
2021年 | 8篇 |
2020年 | 8篇 |
2019年 | 8篇 |
2018年 | 8篇 |
2017年 | 10篇 |
2016年 | 7篇 |
2015年 | 15篇 |
2014年 | 19篇 |
2013年 | 32篇 |
2012年 | 40篇 |
2011年 | 43篇 |
2010年 | 13篇 |
2009年 | 25篇 |
2008年 | 35篇 |
2007年 | 35篇 |
2006年 | 23篇 |
2005年 | 31篇 |
2004年 | 25篇 |
2003年 | 17篇 |
2002年 | 26篇 |
2001年 | 9篇 |
2000年 | 4篇 |
1999年 | 10篇 |
1998年 | 8篇 |
1997年 | 7篇 |
1996年 | 5篇 |
1995年 | 7篇 |
1994年 | 5篇 |
1993年 | 11篇 |
1992年 | 9篇 |
1991年 | 8篇 |
1990年 | 10篇 |
1989年 | 5篇 |
1988年 | 3篇 |
1987年 | 10篇 |
1986年 | 4篇 |
1985年 | 6篇 |
1984年 | 5篇 |
1983年 | 5篇 |
1981年 | 5篇 |
1979年 | 4篇 |
1978年 | 9篇 |
1977年 | 3篇 |
1976年 | 3篇 |
1975年 | 4篇 |
1974年 | 3篇 |
1973年 | 2篇 |
1972年 | 2篇 |
1970年 | 6篇 |
排序方式: 共有616条查询结果,搜索用时 31 毫秒
91.
Yue Zhang János Peti-Peterdi Anna U. Brandes Anne Riquier-Brison Noel G. Carlson Christa E. Müller Carolyn M. Ecelbarger Bellamkonda K. Kishore 《Purinergic signalling》2017,13(2):239-248
Previously, we localized ADP-activated P2Y12 receptor (R) in rodent kidney and showed that its blockade by clopidogrel bisulfate (CLPD) attenuates lithium (Li)-induced nephrogenic diabetes insipidus (NDI). Here, we evaluated the effect of prasugrel (PRSG) administration on Li-induced NDI in mice. Both CLPD and PRSG belong to the thienopyridine class of ADP receptor antagonists. Groups of age-matched adult male B6D2 mice (N = 5/group) were fed either regular rodent chow (CNT), or with added LiCl (40 mmol/kg chow) or PRSG in drinking water (10 mg/kg bw/day) or a combination of LiCl and PRSG for 14 days and then euthanized. Water intake and urine output were determined and blood and kidney tissues were collected and analyzed. PRSG administration completely suppressed Li-induced polydipsia and polyuria and significantly prevented Li-induced decreases in AQP2 protein abundance in renal cortex and medulla. However, PRSG either alone or in combination with Li did not have a significant effect on the protein abundances of NKCC2 or NCC in the cortex and/or medulla. Immunofluorescence microscopy revealed that PRSG administration prevented Li-induced alterations in cellular disposition of AQP2 protein in medullary collecting ducts. Serum Li, Na, and osmolality were not affected by the administration of PRSG. Similar to CLPD, PRSG administration had no effect on Li-induced increase in urinary Na excretion. However, unlike CLPD, PRSG did not augment Li-induced increase in urinary arginine vasopressin (AVP) excretion. Taken together, these data suggest that the pharmacological inhibition of P2Y12-R by the thienopyridine group of drugs may potentially offer therapeutic benefits in Li-induced NDI. 相似文献
92.
Harikrishnan LS Kamau MG Herpin TF Morton GC Liu Y Cooper CB Salvati ME Qiao JX Wang TC Adam LP Taylor DS Chen AY Yin X Seethala R Peterson TL Nirschl DS Miller AV Weigelt CA Appiah KK O'Connell JC Michael Lawrence R 《Bioorganic & medicinal chemistry letters》2008,18(8):2640-2644
2-Arylbenzoxazole 5 was identified as a hit from a fluorescence-based high-throughput screen for CETP inhibitors. The synthesis and SAR investigation employing array synthesis of the A- and B-rings are described. 相似文献
93.
Li JJ Wang H Li J Qu F Swartz SG Hernández AS Biller SA Robl JA Tino JA Slusarchyk D Seethala R Sleph P Yan M Grover G Flynn N Murphy BJ Gordon D 《Bioorganic & medicinal chemistry letters》2008,18(8):2536-2539
A novel series of N1 substituted tetrazole amides were prepared and showed to be potent growth hormone (GH) secretagogues. Among them, hydroxyl containing analog 31 displayed excellent in vivo activity by increasing plasma GH 10-fold in an anesthetized IV rat model. 相似文献
94.
Chugh J Sharma S Hosur RV 《Protein science : a publication of the Protein Society》2008,17(8):1319-1325
Protein self-association is critical to many biological functions. However, atomic-level structural characterization of these assemblies has remained elusive. In this report we present insights into the mechanistic details of the process of self-association of the 136-residue GTPase effector domain (GED) of the endocytic protein dynamin into a megadalton-sized soluble mass. Our approach is based on NMR monitoring of regulated folding and association through Gdn-HCl titration. The results suggest the evolution of a sequence–self-association paradigm. Equally significantly, the study demonstrates an elegant bottom-up strategy that can render large protein self-assemblies accessible to NMR investigations that have remained difficult to date. 相似文献
95.
p63, known to play a role in development, has more recently also been implicated in cancer progression. Mutations in p63 have been shown to be responsible for several human developmental diseases. Differential splicing of the p63 gene gives rise to p63 isoforms, which can act either as tumor suppressors or as oncogene. In this report, we studied the effects of naturally occurring TAp637 mutants on the regulation of p53/p63 and p63 specific target genes. We observed significant differences among p63 mutants to regulate the p53/p63 and p63 specific target genes. Additionally, we observed a differential effect of p63 mutants on wildtype-p63-mediated induction ofp53/p63 and p63 specific target genes. We also demonstrated that these mutants differentially regulate the binding of wildtype p63 to the promoter of target genes. Furthermore, the effects of these mutants on cell death and survival were consistent with their ability to regulate the downstream targets when compared to wildtype TAp63T. In summary, our data demonstrate that p63 mutants exhibit differential effects on p63 and p53/p63 specific target genes and on the induction of apoptosis, and provide further insight into the function of p63. 相似文献
96.
Comparative analysis of the organization and expression patterns of divergent and convergent gene pairs in multiple plant genomes can identify patterns that are shared by more than one species or are unique to a particular species. Here, we study the coexpression and interspecies conservation of divergent and convergent gene pairs in three plant species: rice (Oryza sativa), Arabidopsis (Arabidopsis thaliana), and black cottonwood (Populus trichocarpa). Strongly correlated expression levels between divergent and convergent genes were found to be quite common in all three species, and the frequency of strong correlation appears to be independent of intergenic distance. Conservation of divergent or convergent arrangement among these species appears to be quite rare. However, conserved arrangement is significantly more frequent when the genes display strongly correlated expression levels or have one or more Gene Ontology (GO) classes in common. A correlation between intergenic distance in divergent and convergent gene pairs and shared GO classes was observed, in varying degrees, in rice and Populus but not in Arabidopsis. Furthermore, multiple GO classes were either overrepresented or underrepresented in Arabidopsis and Populus gene pairs, while only two GO classes were underrepresented in rice divergent gene pairs. Three cis-regulatory elements common to both Arabidopsis and rice were overrepresented in the intergenic regions of strongly correlated divergent gene pairs compared to those of noncorrelated pairs. Our results suggest that shared as well as unique mechanisms operate in shaping the organization and function of divergent and convergent gene pairs in different plant species. 相似文献
97.
Four new ternary copper(II) complexes of α-amino acid having polypyridyl bases of general formulation [Cu(l-ala)(B)(H2O)](X) (1-4), where l-ala is l-alanine, B is an N,N-donor heterocyclic base, viz. 2,2′-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2) and 5,6-phenanthroline dione (dione, 3), dipyrido[3,2:2′,3′-f]quinoxaline (dpq, 4), and X = / are synthesized, characterized by various spectroscopic and X-ray crystallographic methods. The complexes show a distorted square-pyramidal (4 + 1) CuN3O2 coordination geometry. The one-electron paramagnetic complexes (1-4) display a low energy d-d band near 600 nm in aqueous medium and show a quasi-reversible cyclic voltammetric response due to one-electron Cu(II)/Cu(I) reduction near −100 mV (versus SCE) in DMF-0.1 M TBAP. Binding interactions of the complexes with calf thymus DNA (CT-DNA) were investigated by UV-Vis absorption titration, ethidium bromide displacement assay, viscometric titration experiment and DNA melting studies. All the complexes barring the complexes 1 and 3 are avid binder to the CT-DNA in the DNA minor groove giving an order: 4 > 2 ? 1, 3. The complexes 2 and 4 show appreciable chemical nuclease activity in the presence of 3-mercaptopropionic acid (MPA) as a reducing agent. Hydroxyl radical was investigated to be the DNA cleavage active species. Control experiments in the presence of distamycin-A show primarily minor groove-binding propensity for the complexes 2 and 4 to the DNA. 相似文献
98.
Critical leaf nutrient concentrations have often been used to diagnose the nutritional causes of crop underperformance. Unfortunately, these diagnostic criteria are not available for mature, tuber-bearing sweet potato plants (the word ‘tuber’ being used to describe a swollen root rather than a swollen stem). The Diagnosis and Recommendation Integrated System (DRIS), however, provides a reliable means of linking leaf nutrient concentrations to the yield of sweet potato tubers, and may be developed for this crop using existing data from regional crop surveys. In the present study, tuber yield and leaf nutrient concentration data from a survey of sweet potato gardens conducted in the Papua New Guinea (PNG) highlands in 2005 were used to establish DRIS N, P, K, and S norms and statistical parameters for sweet potato. Although the database was relatively small, the norms derived for nutrient ratios of key biological significance, i.e. N/S and K/N, were within the expected narrow ranges for higher plants, giving credibility to both the database and the DRIS model. Data from future surveys and field trials may subsequently be used to enlarge the database allowing the refinement of model parameters and hopefully an expansion of diagnostic scope to include other macro and micro-nutrients. As it stands, though, this preliminary DRIS model for sweet potato is possibly the best diagnostic tool currently available for evaluating the N, P, K and S statuses of sweet potato crops in the pacific region. 相似文献
99.
Dynein light chain (DLC8) is the smallest subunit of the dynein motor complex, which is known to act as a cargo adaptor in intracellular trafficking. The protein exists as a pure dimer at physiological pH and a completely folded monomer below pH 4. Here, we have determined the energy landscape of the dimeric protein using a combination of optical techniques and native-state hydrogen exchange of amide groups, the former giving the global features and the latter yielding the residue level details. The data indicated the presence of intermediates along the equilibrium unfolding transition. The hydrogen exchange data suggested that the molecule has differential stability in its various segments. We deduce from the free energy data that the antiparallel beta-sheets (beta4 and beta5) that form the hydrophobic core of the protein and the alpha2 helix, all of which are highly protected with regard to hydrogen exchange, contribute significantly to the initial step of the protein folding mechanism. Denaturant-dependent hydrogen exchange indicated further that some amides exchange via local fluctuations, whereas there are others which exchange via global unfolding events. Implications of these to cargo adaptability of the dimer are discussed. 相似文献
100.
Ch. Srinivas Ch.N.S. Sai Pavan Kumar B. China Raju V. Jayathirtha Rao V.G.M. Naidu S. Ramakrishna Prakash V. Diwan 《Bioorganic & medicinal chemistry letters》2009,19(20):5915-5918
The first stereoselective total synthesis of new natural amide alkaloids 1–3 have been achieved from commercially available starting materials. Wittig olefination, Sharpless asymmetric dihydroxylation, epoxidation, a trans regioselective opening of 2,3-epoxy alcohol, Horner–Wadsworth–Emmons (HWE) olefination and amide coupling are the key steps. The amide alkaloids 1–3 are evaluated for their anticancer activity against colon (HT-29), breast (MCF-7) and lung (A-549) human cancer cell lines for the first time. 相似文献